Novel Therapeutic Targets for Antiarrhythmic Drugs
When I read about the evils of drinking, I gave up reading.”
All of us who see patients are frustrated by the paucity of antiarrhythmic drug options. There are many reasons for this unfortunate situation, some of which, like projected sales volumes and patent issues, are situational and irrelevant to science. Perhaps the most important reason for the lack of choices is an inadequate understanding of pathophysiology. Our inability to appropriately target therapies has led to overtreatment. In essence, we have had to resort to broad spectrum or shotgun therapy to be able to quell arrhythmias in as many people as possible. The situation is analogous to treating pneumonia without knowing the pathogen. The consequence of poorly focused treatment is unintended toxicities, including proarrhythmia. And nobody wants to develop or approve unsafe drugs.
Clearly, there is a need for a more targeted approach to the development and deployment of antiarrhythmic drugs, and this book is an admirable attempt to find a way. The editor solicited ideas from eminent scientists, and their chapters are illuminating and far reaching. In addition to the traditional categorization by ion channel effect, the chapters consider more global issues, such as understanding repolarization reserve and the genetics underlying drug response. Most importantly, the editor has encouraged blue sky thinking in the contributed chapters. What concepts might be used to develop novel drugs in the future? Examples include ryanodine receptors, the sodium/calcium exchanger, and calcium/calmodulin-dependent protein kinase II.
I was particularly encouraged to see an attempt to segregate candidate compounds according to their intended benefit in several disease states. This represents a radical departure from our current approach. Conventionally, we have targeted therapies because we suspect that certain drugs will harm, not because they might be expected to work preferentially in any given disease. Consider heart failure. Dofetilide and amiodarone are used routinely in patients with severe systolic heart failure on the premise that they are effective for the general indication, but even more importantly, because they are safe, as demonstrated in large randomized clinical trials. Similarly, we shun class IC drugs in patients with ischemic heart disease because of uncommon but catastrophic adverse events in landmark trials like the Cardiac Arrhythmia Suppression Trial (CAST).
In a new paradigm, one would hope to target arrhythmias in disease states based on an in- depth knowledge of pathogenesis. For example, there is good reason to believe that redox modification of ryanodine receptors might have a beneficial effect on arrhythmias associated with heart failure. Likewise, drugs that selectively antagonize cardiac sarcolemmal adenosine-5′-triphosphate-sensitive potassium channels may be particularly useful for ischemia-mediated arrhythmias.
The most important weakness of the book is its lack of clinical focus. Undoubtedly, there are many potential mechanisms by which arrhythmias are generated that could be modulated by novel drugs. For example, perturbation of gap junctions is a clear contributing factor to the genesis of a variety of arrhythmias, including atrial fibrillation. Finding effective drugs that target the mechanism is hard enough. Designing clinical trials to prove safety and effectiveness in a properly targeted patient population is particularly daunting. In the absence of proof of concept trials, it is difficult to determine if and how to invest the millions of dollars necessary to bring these concept drugs to the marketplace.
The book also covers some novel topics, including nonpharmacologic manipulation of the autonomic nervous system and the effects of endurance training on susceptibility to sudden death. These topics, though worthwhile and unique, are unlikely to find their way to mainstream acceptance and implementation. Nevertheless, they contribute significantly to our understanding of the pathophysiology of the arrhythmias we struggle to treat.
Some novel concepts have less foundation than others. Dietary omega-3 fatty acids clearly have an effect on cardiac electrophysiology. The evidence to support the idea that dietary supplements have a significant impact on the type or amount of arrhythmia is thin. Once again, moving from solid preclinical information to the clinical realm is the missing link.
Finally, I was somewhat disappointed with the author selection. The authors are impeccable scientists, but not all have worked at the cutting edge of this discipline. I applaud the inclusion of some brilliant industry scientists, but their perspectives on drug development need to be properly balanced by clinicians and trialists who necessarily take a broader view.
Dr Billman should be congratulated for his willingness to take on what is clearly an extraordinarily complex problem area. It is a topic (like drinking) that few of us would dare to harness. The authors, however, made many of the complex discussions not only interpretable, but topical. For example, Lagrutta and Salata produced a chapter on safety pharmacology and regulatory issues in the development of antiarrhythmic drugs in which they provided the reader with references to recent guidelines regarding the development of drugs with electrophysiological effects. Likewise, Aiba and Tomaselli take on the complex issue of remodeling as it relates to ion channels, pointing out how interventions that treat the underlying disease state might impact arrhythmia control. Burashnikov and Antzelevitch develop this theme further in their chapter in which they review so-called upstream therapy. They appropriately point out that angiotensin II, platelet-derived growth factor, transforming growth factor, mitogen-activated protein kinase, matrix metalloproteinases, and peroxisome proliferator-activated receptor-γ may be involved in the genesis of cardiac arrhythmia, and that their inhibition could prevent arrhythmias in susceptible individuals. Unfortunately, we have not seen clear and definitive trial data to support widespread use of modulating agents (like angiotensin receptor antagonists) for general prophylaxis or adjuvant therapy.
Nonpharmacologic therapy of cardiac arrhythmias has developed rapidly over the last 3 decades, in part because pharmacological options have been wanting. Nevertheless, for the vast majority of patients with cardiac arrhythmias, drugs are, and will continue to be, the mainstay of therapy. For those of us who are serious about finding new antiarrhythmic drugs for our patients, including those with atrial fibrillation and malignant ventricular arrhythmias, this book is highly valuable.
Dr Billman has pulled together a wide spectrum of information, for the most part up-to-date and accurate, that summarizes the state of the art and provides a roadmap for future development, at least over the intermediate term. I would recommend this book to my colleagues and fellows, not only as a reference source, but as a compendium of information that summarizes where we are, and most importantly, the path we must take.
Peter R. Kowey, MD
Lankenau Institute for Medical Research
Main Line Health System
Jefferson Medical College
- © 2011 American Heart Association, Inc.